A variety of techniques have been used to introduce foreign genes into cells. Physical methods include co-precipitation with calcium phosphate, electroporation, and particle bombardment. While these direct transfer techniques are adequate in vitro, they are impractical in vivo. Promising in vivo gene therapy relies on a carrier such as viral vectors or liposomes for delivery. There are still lingering safety concerns for viral vectors. Another limitation is the size of the DNA sequences, usually limited to 7-8 kb, that can be incorporated into the viral vector. Liposomes, on the other hand, have low loading level in general. In both cases, there is the issue of cell or tissue specificity for these gene delivery systems.
Controlled drug delivery has significantly improved the success of many drug therapies (Langer, R., 1990, New methods of drug delivery, Science, 249:1527-33; Poznansky, et al., 1984, Biological approaches to the controlled delivery of drugs: a critical review, Pharmacol Rev., 36:277-336). A major goal of drug delivery is to localize the drug to the target site. These targeted delivery systems often take the form of injectables composed of liposomes (Gregoriadis, G., 1988, Liposomes as Drug Carriers, New York: Wiley; Litzinger, et al., 1992, Phosphatidylethanolamine liposomes: drug delivery, gene transfer and immunodiagnostic applications, Biochimica et Biophysica Acta, 1113:201-27) and microspheres made of proteins (Cummings, et al., 1991, Covalent coupling of doxorubicin in protein microspheres is a major determinant of tumor drug deposition, Biochem. Pharm., 41:1849-54; Verrijik, et al., 1991, Polymer-coated albumin microspheres as carriers for intravascular tumor targeting of cisplatin, Cancer Chemother. and Pharm., 29:117-21; Tabata, et al., 1988, Potentiation of antitumor activity of macrophages by recombinant interferon alpha A/D contained in gelatin microspheres, Jpn. J. Cancer Res., 79:636-646), polysaccharides (Rongved, et al., 1991, Crossed-linked, degradable starch microspheres as carriers of paramagnetic resonance imaging: synthesis, degradation, and relaxation properties, Carbohydrate Res., 145:83-92; Carter, et al., 1991, The combination of degradable starch microspheres and angiotensin II in the manipulation of drug delivery in an animal model of colorectal metastasis, British J. Cancer, 65:37-9), and synthetic polymers (Davis, et al., 1984, Microspheres and Drug Therapy, Amsterdam; Eldridge, et al., 1991, Biodegradable microspheres as a vaccine delivery system, Molec. Immunology, 28:287-94; Pappo, et al., 1991, Monoclonal antibody-directed targeting of fluorescent polystyrene microspheres to Peyer's patch M cells, Immunology, 73:277-80). Polymeric systems share some of the advantages of liposomal systems such as altered pharmacokinetics and biodistribution. While liposomes might have better prospects of biocompatibility and potential for fusion with cells, polymeric microspheres have more controllable release kinetics, better stability in storage, and higher drug-loading levels for some classes of compounds.
There is a need in the art for a DNA delivery system which can provide controlled release, is simple to make, is stable, is cost effective, has a high DNA loading level, and is relatively non-immunogenic.